This invention in general relates to novel pharmaceutical compositions for acid labile substances as well as for methods of making such.
Substituted benzimidazoles are substituted sulfoxides which are potent inhibitors of gastric acid secretion. Such substituted sulfoxides are described for example in EP 0005129. These compounds are susceptible to degradation and/or transformation in both acid and neutral media. The acidic decomposition of these acid labile compounds is due to an acid catalyzed reaction described by G. Rackur et al., in Biochem. Biophys. Res. Commun. 1985: 128(1). P477-484.
In order to provide a pharmaceutical composition containing such acid labile substances which is not degraded in the gastrointestinal tract, the acid labile substances must be enteric coated. However, pharmaceutically acceptable enteric coating materials are acidic in nature or contain acid reacting groups. Therefore, if the acid labile substances are directly covered by these enteric coating materials, the acid labile substance rapidly degrades.
U.S. Pat. Nos. 4,853,230 and 4,786,505 describe enteric coated pharmaceutical formulations of acid labile substances for oral use, where the cores contain acid labile drugs mixed with alkaline reacting substances. This is then coated with a first separating layer which is rapidly disintegrated in gastric fluid and a final enteric layer. However, the alkaline reacting substances in the core do not completely protect the acid labile substances from degradation and thus additional pH buffering substances are required. These formulations may also contain aluminum, potassium, sodium, calcium and magnesium which compounds or composites may be of concern for oral ingestion in humans.
U.S. Pat. No. 2,540,797 describes an enteric coated pharmaceutical in an oral dosage form, where the enteric coating is combined with a second and/or first coating of water insoluble xe2x80x9cwaxxe2x80x9d layer. This coating is not suitable as direct contact with acid labile substances as it will result in degradation of the acid labile active.
WO No. 85/03436 discloses a pharmaceutical preparation in which the core contains active drugs mixed with buffering compounds such as sodium dihydrogenphosphate which maintains a constant pH. A coating material is used to provide a constant rate of diffusion of the pharmaceutical active. However, this formulation is not suitable for acid labile compounds where a rapid release in the small intestine is required. The direct application of an enteric coating onto the pharmaceutical active would adversely influence the storage stability of the acid labile compounds contained therein.
DE-A1-1 204 363 describes a three layer coating method for pharmaceuticals. The first coating layer is a surface membrane soluble in gastric but insoluble in intestinal juice. The second coating layer is soluble at all physiological pHs and the third coating layer is an enteric coating. This method is complicated and is also not suitable for acid labile compounds such as substituted benzimidazoles where rapid release of the drug in the small intestine is required, as it results in a dosage form which is not dissolved in gastric juice and dissolves slowly in the small intestine.
There was therefore a need to develop a pharmaceutical composition for acid labile substances that adequately protected the acid labile active prior to its being released in the small intestine. Accordingly, a novel pharmaceutical composition was developed for the delivery of acid labile substances to the gut which differs form known compositions and delivery mechanisms in the type of stabilizer(s) utilized, the mechanism(s) of stabilization used in the core containing the acid labile compound(s), by the type of protector coat applied to the core(s), the mechanism(s) by which the protector coat elicits it""s protective action and the type of enteric coating compound(s) used in the composition. These lead to a different mechanism by which the acid labile drug is released in the small intestine to provide a stabilized acid labile compound composition.
The present invention provides an enteric coated dosage form of a selected acid labile compound, in particular proton pump inhibitor compounds which decrease production of acid in the gut. Such compounds include but are not limited to a omeprazole, 5-methoxy-2-(4-methoxy-3, 5 dimethyl-2-pyridinyl methyl sulfinyl-1H-benzimidazole, lansoprazole, 2-(2-diriiethylaminobenzyl)sulfinyl-benzimidazole and their related compounds such as their salts which rapidly disintegrate in the small intestine.
The novel pharmaceutical composition comprises an acid labile compound or an alkaline salt of the labile compound. The composition optionally comprises acid sequestering compound(s), and further comprises disintegrants and at least one coating layer which is swellable and/or permeable at physiological pH (preferably  greater than 5.0). This first coating layer separates and protects the core containing the acid labile active from the outer enteric coating layers.
According to an object of the present invention there is provided a pharmaceutical composition comprising:
xe2x80x94 about 1 to 75% by weight acid labile compound;
xe2x80x94 up to about 5% by weight disintegrant;
xe2x80x94 at least one protector coat layer used to separate and protect the acid labile substance from acid reacting groups and gastric juice; and
xe2x80x94 at least one enteric coat layer which surrounds the protector coating layer and ensures delivery of over 80% the acid labile substance to the small intestine.
Optionally, the composition may additionally comprise not less than about 0.1% acid sequestering compound.
According to another object of the present invention is a method for preparing the novel pharmaceutical composition of the present invention.
The novel formulation of the present invention demonstrates excellent resistance to dissolution in acid media and dissolves rapidly in neutral to alkaline media. The novel acid labile substance formulation has a good stability during long term storage.
The novel pharmaceutical composition is well suited for oral administration in a dosage unit form.